Outlive

Summary

This book is a guide to living a long and healthy life. It is about increasing lifespan, our "good decades", more than it is about living longer per se. It focuses on the four horsemen (cancer, metabolic syndrome, alzheimers and cardiovascular diseases), explaining how they develop and how they, eventually, kill most humans today. The main idea is that of a Medicine 3.0, more focused on prevention rather than cure, that tracks and stops these diseases in their early stages before they develop. Because one thing that all the horsemen have in common is that they start long before the first symptomps appear and that it is way too late to act on them, once the symptoms do appear. Then the diseases have already progressed too much and are usually lethal, even with our arsenal of modern Medicine 2.0 curative tools.

Preventing the hoursemen, while not easy, is definitely possible. However, it needs behavioral change. Mostly more exercise and an active lifestyle. The idea is that fitness decreases when we get older and that even basic activities become impossible, once we get old enough. Attia therefore argues, that we have to start with the end in mind. First think of the 10 activities that we want to be able to do when we are 100 years old–our personal Centenarian Decathlon. From there we can estimate the fitness level that we have to reach now when taking into account the decline of aging itself. The takeaway: You need to be surprisingly fit, like top 0.1% level athlete fit. And fit, has a very clear definition according to Peter Attia. It's about being strong (grip strength as a proxy), flexible, having a high VO2 max, and in good balance. ALL of these are necessary. Training for this requires serious time commitment, but it's the single best thing that we can do for increasing our healthspan. And best of all, there is no upper bound: fitter means better for longevity. Grip strength and VO2 max are the best predictors we have of getting really old.

The last little bit of the book I found really surprising. In it Attia focuses on mental health. The main idea here is that, if you do all the things described above and live very long and healthy, this is not enough. You also need sothing to live for: friends, goals, family, emotional support networks. If you don't, it's not worth it. In other words, becoming a lonely, bitter, but otherwise totally healthy person is not the way to go. This idea reminds me a lot of Victor Frankl's book Man's Search for Meaning, how we need a reason for existence.

Overall Peter Attias book is eye opening. It explains how to live longer, with clear, achievable goals and strategies. Reasoning from first principles, he explains how the four horsemen that kill us right now can be prevented, and that what this boils down to is simply this: exercise (and good sleep and little stress). Finally he points out that this is urgent, the earlier we start doing this, the better, because time is key.

I would add that the second best is better sleep and the third best is reduction in stress.

Key Takeaways

• The Four Horsemen are slow and progress in the background, we need to fight them early
• Exercise is key => the more the better, but needs to be the right exercise, strength, VO2 max, balance, flexibility
• You need to be much fitter than you think for your Centenarian Decathlon, because every decade decreases performance
• Enough (and good quality) sleep and low stress are important as well
• Healthspan is worth nothing if your life itself sucks, focus also on emotional health

Detailed Notes

These notes are long and comprehensive of the main themes in the book. You should go read the whole thing as well.

Introduction

Anecdote of a guy throwing down eggs from a building and Peter Attia catching them before they hit the ground. Doctors do the same, they become exceptional egg catchers, but they don't take out the maniac who keeps throwing them from the roof, the book is about that. Taking out the thing that causes diseases and death: aging.

Chapter 1 - The Long Game, From Fast Death to Slow Death

Fast: Car accidents, gunshots, knife wounds Slow: Cancer, Cardiovascular disease, Alzheimer's

Cancer doesn't care how rich you are. Or who your surgeon is, really. If it wants to find a way to kill you, it will.

Focus is on longevity. Longevity doesn't mean to live until 120 or 150. Death comes. You don't want long life, you want a healthy life.

Longevity is malleable and not 100% tied to genetics.

Nowadays slow deaths make up a bigger percentage of deaths than ever.

Four Horsemen: Heart disease, cancer, neurodegenerative disease, metabolic dysfunction

How long you live vs. how long you remain healthy Lifespan vs. Healthspan

Healthy is not just free of disease it's about being able to function as well as possible, physically and mentally.

The only way to not lose out on possible healthspan is to start acting on it now.

Doctors are good at fixing fast death, but not at fixing slow death. Slow death has to be fixed 20 years before it happens. The problem is that slow death is not diagnosable like a gunshot is. When it is diagnosable it's already 20 years too late. It's complex, non binary, subtle.

The four Horsemen are disease processes. They are complicated, have multiple factors interacting with one another and are therefore hard to understand completely. However multiple factors of each Horsemen are shared and can be reduced or even eliminated.

Current Ideas are often misguided and need correcting. Examples: Mainstream root causes of horsemen are not understood correctly. Ideas about nutrition e.g. cholesterol are so simplified to be practically useless. There is a liver condition that many people have, which can lead to type 2 diabetes. Metabolic derangement raises risk for all four Horsemen. Diets are useful for some but not for all. You need understanding of nutritional biochemistry. Protein is important. More important as we age. Exercise is too. It's important to have enough and enough is a high bar. And it has to be of the right type otherwise it can do more harm than good. Longevity without emotional health is meaningless. Part of Emotional Health is Loneliness. Close friends and relationships are as important if not more so than bodily health.

The problem of our scientific understanding of aging is applying it outside of the lab to real humans at scale.

The goal: Extend lifespan by a decade and healthspan by two. This is possible with good habits and today's knowledge applied correctly.

Chapter 2 - Medicine 3.0 - Rethinking Medicine for the Age of Chronic Disease

Medicine has a culture resistant to change in it. It's conservative.

Book Recommendation: On Death and Dying – Elisabeth Kübler-Ross

Medicine needs a better, more quantitative understanding of risk.

Risk is not something to be avoided at all costs; rather, it's something we need to understand, analyze and work with.

Scientific method: guess, test the guess, guess again but better. Repeat.

Book Recommendation: Extra Life – Steven Johnson

Chronic diseases are small risks cumulatively compounding over time into catastrophes.

Technology is too slow in catching up with our vision of how things could be. We want nanobots healing all disease but we don't have them yet. We need to make work with what we have now.

Medicine has been progressing through 3 phases, 1.0, 2.0 and 3.0 which is just now coming. Age old "wisdom", then evidence based scientific medicine and now personalized, correct risk assessment based, preventative, trying to maintain healthspan => medicine 3.0.

We want more out of life than simply the absence of sickness or disability. We want to be thriving, in every way, throughout the latter half of our lives.

We spend more money on curing human suffering than preventing it. And that's a tragedy.

Iceberg Metaphor: Sensing and avoiding potential catastrophes in the way, while assessing that potential course corrections don't lead to new collisions later. If avoiding one catastrophe but steering into another, then it's not a good course correction.

Medicine 3.0 demands more action of the patient. Confronting truths and problems and acting on them with behavior change.

Chapter 3 - Objective, Strategy, Tactics - A Road Map for Reading This Book

We need to plan for the last decades of our lives. Well in advance, and then prepare for that time, by making decisions and acting on those decisions.

Ask: What do you want to be doing when you're really old? Then work backwards. What do I need to do so that I have the highest chance of still being able to do that.

It's not enough to not do anything bad. You have to do good things, to maintain or improve your capabilities, against the toll of aging. You want the below dashed line curve.

Tactics follows from strategy which follows from an objective. What is the objective of medicine 3.0? To extend healthspan. What is the strategy to get there?

Complex problems need more strategy.

Paper: 2013 - hallmarks of aging paper

Period of decline in older people is like dying in slow motion. Health span is not binary you want to be on the high end of the spectrum. 3 vectors of decline - mental acuity, physical body, emotional health. For healthspan to be meaningful you need to avoid all 3 vectors.

If you want to do a certain activity in old age, you need to be above a certain VO2 max well before that age.

Even minimal activities that we take for granted now will be taken away when we get older if we don't build and maintain a solid basis of fitness starting now.

Tactics have to be woven into the daily lives. They need to be habits.

Medicine 3.0 has 5 different categories of tactics: exercise, nutrition, sleep, emotional health, and exogenous molecules

Exercise has core components: strength, stability, aerobic efficiency and peak aerobic capacity. You need to increase limits in all of them as much as possible. 

Nutrition: what you eat matters, but how much you eat matters more. Not too much, not too little, finding the goldilocks zone

Sleep: good sleeping habits are important. Read Why We Sleep by Mathew Walker 

Emotional Health: trickiest of all, maintain, mend and build relationships that are meaningful, always

There's a blind spot in evidence based medicine, long lived disease processes are hard to study with randomized controls because they take decades to unfold. The shift needs to be from evidence based to "evidence informed risk adjusted precision medicine".

A good question to ask: what do centenarians have in common? Combine with cross evolutionary animal studies, and disease as well as molecular models from human studies. Lastly we add Mendelian randomization studies, where genes with specific effects are linked to people who have certain health issues. This way you can determine causal links, i.e. do people with say more LDL cholesterol, a higher or lower chance of cancer?

From all of that, one thing is absent. Certainty of knowledge. Instead it becomes about managing risks against each other. Risk of being wrong vs. risk of being right but not acting out of fear of adverse consequences. Medicine has to become like investment strategies. You want better than average returns on your investments, so you do with health. This idea is called alpha. Higher alpha is better.

Unorthodox but reasonable lifestyle changes can drastically improve your chances for longevity.

Chapter 4 - Centenarians - The Older You Get, the Healthier You Have Been

We yearn for there to be some sort of "secret" to living a longer, healthier, happier life.

Such a secret doesn't exist. But the fascination of people doing odd stuff and still becoming old still holds. This is not alpha though. The question is not of what they do differently but what centenarians have in common.

For every super centenarians (person aged 110+) there are nine billionaires.

Some of centenarians luck is based on genes. We don't know exactly how much.

Can we emulate their phenotype though? Because centenarians are generally pretty healthy and fit. Not like you would expect 100 year olds to be like. Men over 100 tend to be fitter than women. Likely because frail men get weeded out by age related diseases like cardiovascular disease much much earlier. Also because their muscle mass is higher it makes them more cardiovascular healthy in old age.

Paper: The Older You Get The Healthier You Have Been - Pearls et al

Centenarians are often healthier than their younger peer groups. They compress morbidity to a small fraction of time at the very end of their very long lives. Medicine 3.0 is about mimicking or causing what centenarians have because of luck or genes, but intentionally.

What we want for ourselves: to live longer with good function and without chronic disease, and with a briefer period of morbidity at the end of our lives.

Evolution doesn't select on genes for longevity because they don't help reproductive success directly.

Some genes have an effect, mostly a detrimental one. Example is APOE, FOXO3, CETP, APOC3. But in the end its hundreds or thousands of genes each conferring little advantages. There are a lot of ways to become really old.

If we want to outlive our life expectancy and live better longer, we will have to work hard to earn it–through small incremental changes.

FOXO3 can be activated through environment, like when exercising or low in nutrients. It activates cell maintenance mode.

The Centenarians secret is one word: resilience. They grow old besides doing bad things like smoking, drinking and eating shitty foods.

Chapter 5 - Eat Less, Live Longer? - The Sciences of Hunger and Health

Podcast: Tim Ferriss - Easter Island Episode

Rapamycin - compound that slows cell growth and division. It acts on the mTor receptor. mTor is conserved in all animals. It regulated cellular metabolism in times of food shortage. Rapamycin is suggesting your body that it's starving.

Nutrients high mTor on, growth and reproductive axis on. Nutrients low, mTor off, cells go into recycling/longevity mode.

Article: Antibiotic Delayed Aging in Experiments with Mice - New York Times

Calorie restriction is the most potent longevity enhancing tactic we know of.

Limit caloric intake while maintaining nutrients.

Other pathways related to mTor: AMPK - activated to lack of nutrients and exercise. It helps cells conserve and use other sources of energy. Produces new mitochondria. AMPK shuts down mTor. And induces autophagy. Cells self eating to recycle proteins.

Rapamycin has immune suppression effects if given daily in low doses. If given cyclically in higher doses, these effects vanish, making it a possible treatment for healthy people. Rapamycin is an immune modulator. It can both increase and decrease immune system function depending on circumstances.

mTor is made up of 2 complexes. mTorC1 and mTorC2. Only inhibiting mTorC1 is enough for anti aging effects. High cyclical dosage of rapamycin does that without targeting mTorC2 as much.

Paper: Papers by Kaeberlein group seem to be good

Metformin is another compound that seem gero protective. It keeps people healthy.

Paper: TAME Trial - Targeting Aging With Metformin

Chapter 6 - The Crisis of Abundance - Can Our Ancient Genes Cope with Our Modern Diet?

NASH and NAFLD (non alcoholic fatty liver disease) - basically fatty liver from over consumption of calories. Many people have it and it's a precursor to type 2 diabetes. If this happens ALT enzyme and cholesterol also increase.

In the twenty-first century, "average" is not necessarily optimal.

Livers can regenerate quite well. But once they have scar tissue that's not longer the case. Liver cirrhosis is irreversible. NASH can lead down that path.

Metabolic dysfunction is a general problem. Diabetes, pre-diabetes, NAFLD, hyperinsulinemia are all things resulting from it. And so do the horsemen. Especially cardiovascular disease.

Metabolic Syndrome: High Blood Pressure ( >130/85) High Triglycerides (>150 mg/dL) Low HDL cholesterol (less than 40 mg/dL in men or less than 50 mg/dL in women) central adiposity (obesity) elevated fasting glucose >110 mg/dL

Obesity is not the cause. It's a symptom of other problems.

Metabolic Syndrome is not about how much you weigh. Even thin people can have NASH and metabolic syndrome.

Glucose Homeostasis: food carbohydrates => glucose => blood glucose => glycogen in the liver => blood glucose => cellular glucose (all while keeping blood glucose stable)

Liver is titrating about a teaspoon of sugar in the entire bloodstream at all times.

Where to store energy in food is determined by hormones, like insulin. Two choices, glycogen (in muscle or liver) + fat (as triglycerides in subcutaneous OR organ fat)

Subcutaneous fat actually plays an important role in maintaining metabolic health.

Paper: Gerald Schulmann transplanting fat tissue into obese mice to cure Metabolic Syndrome

Fat cells sucking up glucose from the blood is a good thing. Fat is a metabolic buffer zone in a way. Problem happens when fat cells are full because the buffer is overflowing because there is nothing going out of the buffer.

Don't over eat. Have time of fasting and high intensity exercise where fat stores can be depleted again.

Fat spilling over from fat cells is the main problem of metabolic dysfunction. It accumulates in the wrong places essentially turning into poison. Accumulating fat between organs is called visceral fat and it puts out inflammatory cytokines. TNF-alpha and IL-6. The immune system response near to organs, all the time, is not nice.

Sub cutaneous fat storage capacity varies hugely between individuals. Thin people might be more at risk, because they have less places to store subcutaneous fat. It's easier for them to fill up their fat stores and end up with visceral invisible organ fat instead of the visible subcutaneous fat rings of other people.

Their is a DEXA scan. You should do it annually to know how much visceral fat you have. A few kilograms is more than enough to cause serious problems.

Fat accumulating in muscle cells disrupt insulin signaling networks. The muscles can't take up any more sugar in response to that, which causes the sugar to be stored as even more fat. A spiral starts. Also the pancreas which needs to produce insulin becomes worse at doing so because of the fat + needs to produce more than ever, and eventually pancreatic beta cells start dying. Eventually all cells are insulin resistant + you lose the ability to produce it at which point all calories have to be stored as fat.

Paper: all the work by Gerald Shulman on fatty tissue

Other hormones are also involved in moving around sugar and fat. Testosterone, estrogen, hormone-sensitive lipase, and cortisol. Cortisol is interesting because that explains the links between obesity and lack of sleep or stress. They both raise cortisol levels. Cortisol is especially bad too, because it lowers subcutaneous fat and replaces it with visceral fat.

Insulin is a one way gate for fat storage. It only makes it go in, not out. It's about fat storage.

Hyperinsulinemia is a cause of weight gain. Metabolic derangement usually comes before obesity. By age 30 or so, most people have literally killed their metabolism with their diets which is why they start to become fat. It's nothing to do with age. It's diet accumulated damage.

Nearly half of the population is either on the road to type 2 diabetes or already there.

Evolution is no longer our friend, because our environment has changed much faster than our genome ever could.

Access to unlimited calories is the problem.

Fructose is a problem, because it has a propensity to be turned into fat. Fructose is metabolized different than other sugars. Fructose metabolism creates uric acid. Which creates among other things the disease gout. But even more interesting uric acid builds up in humans because we lack the enzyme uricase. Basically when uric acid builds up it can help turn fructose into fat storage. That's why humans lost the gene for uricase. Because fat storage in colder climates was more important. Summer => eat fruits and get fat, winter => draw from fat storages

Fructose in today's diet is everywhere in shitload amounts. The problem with fructose is in speed of absorption. Fructose spikes are problematic. Hence it's hard to get fat from only fruits. They release the fructose to slowly into the blood because of fibers. Fructose is metabolized different from glucose. It can consume "unlimited" amounts of ATP, signaling cells that we are still hungry because there is not enough ATP available. Glucose metabolism has a break built in so that this doesn't happen.

Fructose tricks our metabolism into thinking that we are depleting energy—and need to take in still more food and store more energy as fat.

This trick is AMPD - the evil twin of of AMPK. It blocks the satiety hormone leptin, it makes us keep eating and stay hungry, because high levels of fructose means, high levels of food around and high levels of AMPD ensure that we keep eating, keep stocking up, keep growing fat and muscles. Leptin/Ghrelin and the reproductive vs. maintenance axis.

See more Edubily.

Thought: This also perfectly explains why the food industry tries to put fructose into everything they can. They try to abuse this pathway (and others related to blood sugar) to boost sales.

Question: Does this explain why I can eat so much Muesli without feeling full quickly? Because of it's high fructose content from the Yoghurt and the Fruits?

Watch for Uric Acid, Homocysteine, chronic inflammatory markers, and ALT liver enzymes, ratio triglycerides to HDL cholesterol (1:1), VLDL, insulin

OGTT - oral glucose tolerance test, should not lead to postprandial insulin spikes, else you're in trouble

Hyperinsulinemia is a bona fide hormonal disorder. It should be treated as such.

We have a lot of control over the variables affecting metabolic syndrome. How we exercise, what and how much we eat and how much we sleep are all within our control. But in our modern environment this requires a lot of effort. We are all undermoved, underslept and overfed.

Chapter 7 - The Ticker - Confronting–and Preventing–Heart Disease, the Deadliest Killer on the Planet

Heart attack is really deadly. The best most descriptive symptom of it is literally sudden death.

Atherosclerotic disease should be the tenth leading cause. Not the first.

Cholesterol is essential to life. It's a building block in different molecules, like hormones or the lipid bi-layer that makes up cell membranes. Because it's a lipid it can't travel freely in the blood. It is carried around in proteins, LDL and HDL. High and low density lipoprotein. Inside is lipid, outside is protein, hence the whole us water soluble. It's like a tiny spherical "ship" to shuttle around fats, like cholesterol. The difference in amount of protein vs. fat gives their names. HDL carry more protein relative to fat, LDL less. Both are encased in another layer of proteins for transport. Apolipoproteins. apoA for HDL and apoB for LDL. Both exchange fats with one another. So cholesterol can go from HDL to LDL and vice versa. The problem is with the apoB variant. Atherosclerotic disease is driven by apoB proteins.

Cholesterol in food plays no role in atherosclerotic processes. Cholesterol is produced by our own cells not taken up from food. It does in animal model organisms like rabbits or chicken, but humans lack the ability to absorb cholesterol from foods. We know that since 1997.

Atherosclerotic disease starts developing in our teens and early twenties. Holy shit.

Book Recommendation: Atlas of Atherosclerosis Progression and Regression – Herbert C. Stay

LDL and HDL in the bloodstream can penetrate the endothelium barrier and get to the sub-endothelial space. The problem is apoB characteristic proteins, like LDL, can get stuck there. On its own this is not bad, but the fat that they carry can become oxidized by coming into contact with a reactive oxygen species (ROS) at which point they become basically toxic to the surrounding tissue. Smoking and high blood pressure are the two biggest risk factors. Because both of them damage endothelial tissue and therefore make it easier for apoB variant lipoprotein to enter the sub-endothelial space.

The amount of apoB variant carrier proteins for cholesterol is much more important than the total cholesterol level.

When enough apoB oxidized Cholesterol gathers in the sub-endothelial space, the immune system kicks in due to the cell damage and macrophages start eating the oxidized fat carriers. Problem is these cells also can't properly handle the huge amounts of oxidized fat and end up kind of transforming into a different type of cell known as "foam" cell. Enough of them gathering in an endothelial wall give you a "fatty" streak you can see with the naked eye during autopsy. This fatty tissue has nothing to do in the endothelial space. It's not good for the job of being an artery wall with the shifting pressure and all. This sort of fatty tissue is called a lesion or plaque. And a third of 20 year olds already have them. This is bad.

HDL can actually reverse some of this process. It can take up some of the cholesterol in the foam cells and shuttle it back into the bloodstream. This is why HDL is good. Because it helps in delipidation. That's why the plaques in the 20 year olds don't develop more quickly into full blown heart attacks. It takes time to grow more and more serious and likely. But the role of HDL is not well understood yet. Simply raising it with drugs doesn't affect cardiovascular risk. It's not about it's concentration but it's function. Longevity genes all play a role in HDL production. After some time the lesions of fat start calcifying, this is the body attempting to give structural strength back to the arterial wall. This is visible on calcium scans. The problem is if the fat gets lose, the arterial wall breaks at that point you have a problem.

Thought: This is serious and I need to bring all of this to my dad to at least stop his destructive behavior. Maybe we can make him cardiovascular stable so he doesn't die of a heart attack soon. Plan: get him to stop smoking, get him a CT angiogram, elevated LP(a), and an apoB test, then create exercise program, and plan better diet system together with Enes. Also give him statins. Look at page 141/142.

LP(a) - if LDL fuses with apo(a) this toxic shit results. It's basically an aggregator for you guessed it - oxidized lipid molecules. And of course it's an apoB family protein.

Paper: Peter Libby, Nature Reviews 2019: Atherosclerosis in absence of LDL-C concentrations

Treat atherosclerotic disease by reducing apoB as much as possible = eliminate it. The earlier the better, the lower the better.

Chapter 8 - The Runaway Cell - New Ways to Address the Killer That Is Cancer

Book Recommendation: The Transformed Cell - Steve Rosenberg

Cancer is the second leading cause of death. Even with a lot of funding that has poured into it, it still kills many many people and is somehow still not properly understood.

Three part strategy to deal with cancer: prevention, early detection, new medication especially immunotherapy based variants.

One major reason why cancer is so deadly—and so scary—is that we still know relatively little about how it begins and why it spreads.

Cancer cells don't grow faster, they just don't stop. The big problem of stopping cancer is their ability to spread. They become systemic, spreading through the whole body.

Cancers are really different from one another and there are millions of genetic variants. Tumors are complex.

Paper: Cancer Genome Atlas - 2008

Tumors had 100 or more mutations on average and the types of mutations appear to be somewhat random. So no two cancers share the same genome or are alike. It's the combination of random mutations that causes cancer.

Metastasis is not well understood and selectively killing cancer cells is terribly difficult because they are so much like normal human cells in almost every aspect.

Book Recommendation: Mortality - Christopher Hitchens

The Warburg Effect - cancer cells consume up to 40 times more glucose than normal cells because they use glycolysis instead of the Krebs cycle to produce ATP. The question is why? The reason is that cancer produces small molecules needed for proliferation in this way. It's a sneaky way to abuse glucose to manufacture building blocks for multiplying, when you as a cell really shouldn't.

Metabolic Syndrome increases cancer chance.

Book Recommendation: The Emperor of All Maladies - Siddhartha Mukherjee

Insulin and IGF-1 should be low.

Paper: Nature 2018 - Mukherjee and Cantley, ketogenic diet + PI3K inhibitors

Metabolic state can affect efficacy of treatments. Fasting mimicking diets help chemotherapy to work and feel better.

Chimeric antigen receptor T cells - car-T therapy. Basically genetically engineered immune cells of the patient that have the correct cancer sensing antigens grafted onto them genetically.

Immunotherapy has come a long way but it still has a long way to go. It's just effective against specific cancer types so far and expensive because it has to be engineered again for every new patient.

Cancer screening suffers from false positives if the incidence in the tested population is low. It's very important to test with multiple tests, cross confirming the findings, and reducing the chance of false positives. The earlier, the better.

Blog Post: Bayesian Statistics for Cancer Tests Rant by SlateStarCodex

Problem of sensitivity vs. specificity. Increasing one usually decreased the other. Less false negative usually means more false positives because the test is more aggressive.

New cancer screening methods involve blood testing, called liquid biopsies. Essentially a test for cell-free DNA in the blood being abnormal, finding the needle in the haystack. Grail, sub company of Illumina is pursuing this. Giant DNA sequencing apparatus throughout is necessary but luckily DNA sequencing is becoming stupidly cheap, stupidly fast. Kind of like Moore's Law.

We don't know how to prevent or cure cancer and this is the horseman hardest to eliminate.

Paper: Liberti and Locasale - 2016 - tumor microenvironment pH lactic acid

Book Recommendation: Breakthrough - Charles Graeber

Chapter 9 - Chasing Memory - Understanding Alzheimer's Disease and Other Neurodegenerative Diseases

Alzheimer's has a genetic risk variant from gene from the APOE e4 allele.

We don't know how to reverse Alzheimer's and don't have a medication that is effective either.

Alzheimer's disease is linked to plaques of Amyloid Beta protein accumulating in the brain. Amyloid Beta is a misfolded protein from miscleaved APP. It attracts Tau, another protein which creates inflammation.

However removing the Amyloid Beta is not enough. Alzheimer's still develops.

Amyloid Beta is not sufficient for causing Alzheimer's and it's not necessary either.

Book Recommendation: Alzheimer's Treatment, Alzheimer's Prevention: A Patient and Family Guide

Nutrition and lifestyle based interventions can reduce chance of developing neurodegenerative diseases.

Behaviors and skills are mediated by multiple networks in the brain. Saying that we are of two minds about something is not inaccurate.

The more of these networks and subnetworks that we have built up over our lifetime, via education or experience, or by developing complex skills such as speaking a foreign language or playing a musical instrument, the more resistant to cognitive decline we will tend to be.

This idea is known as cognitive reserve. Building cognitive reserve means learning highly complex and varied things over an entire lifetime. Both in movement as well as in other domains.

Paper: Alzheimer, Age related disease, 1968 - Blessed, Tomlinson, and Roth

No computer possesses anything approaching the multidimensionality of the human self.

Alzheimer's and other Neurodegenerative diseases might be caused by lack of energy in neurons. Many risk factors of Alzheimer's are related to reduced blood flow in the brain. This hypothesis is known as the neuronal energy crisis hypothesis.

Insulin administered directly to the brain intranasally helps against symptoms of cognitive decline.

Metabolic and vascular causes of dementia might be causally overlapping.

Against neurodegenerative disease, ketogenic diet makes sense. Ketone usage doesn't decline so the brain has two fuel sources for energy - ketones and glucose.

Exercise is even more important. Strength is a proxy for neuronal health. Grip strength specifically is a proxy for general strength. Better grip strength => lower chance for dementia.

Sleep and stress are also important.

Oral health is connected to overall health. Flossing and regular brushing are important.

Principles:

1. What's good for the heart is good for the brain
2. What's good for the liver is good for the brain
3. Time is key.
4. The best tool is exercise.

Chapter 10 - Thinking Tactically - Building a Framework of Principles That Work For You

I would much rather live in our modern world, where I worry about losing my iPhone or missing a plane flight, than endure the rampant disease, random violence and lawlessness, that our ancestors suffered through for millennia.

Our world is filled with dangers our body and genome is not equipped to handle. That's why we need to use cunning strategy and tactics to overcome these shortcomings.

The broad strategy is clear. Exercise, Nutritional Biochemistry, Sleep, Emotional Health, Drugs

But the specific tactics that follow from that are hard, there are too many options.

Essentially we want simple rules that can be adapted to circumstances with measurable feedback loops. Even small changes and adjustments over time can have serious compounding effect.

It's not about giving detailed personalized instructions. It's about providing a framework of thought to make better data driven decisions. It's also about tinkering, about adjustment over time as our circumstances and bodies change.

We are not bound by any specific ideology or school of thought, or labels of any kind. We are not "keto" or "low-fat", and we do not emphasize aerobic training at the expense of strength or vice versa.

Thought: This is the Edubily approach. Use understanding to improve tactics.

Our only goal is to live longer and live better—to outlive. To do that, we must rewrite the narrative of decline that so many others before us have endured and figure out a plan to make each decade better than the one before.

Chapter 11 - Exercise - The Most Powerful Longevity Drug

The effect of exercise is GIGANTIC. More exercise is almost certainly better. Varied exercise is important too. Strength, aerobic fitness, aerobic peak capacity, and balance all need to be improved. Regular exercise decreases risk of all major death causes by 14%.

Structured exercise programs are important. Exercise can be done "better". But everything is better than no exercise.

VO2max is single best predictor of longevity. Good is around 60 ml/kg/min. The higher the better. It's a good correlate for fitness. Poor cardiorespiratory fitness is a greater risk than regular smoking.

Paper: Journal of American College of Cardiology - exercise in veterans 2022 - Kokkinos et al.

There is no upper limit to the correlation of VO2MAX to longevity. The more the better. Even better: it can be increased with training.

The same or a similar correlation holds true for muscle and longevity. It's not about muscle mass but musclestrength.

The fitter you are, the lower your risk of death.

Exercise performs better than drugs in clinical trials for cardiovascular disease or diabetes.

Exercise helps the human "machine" perform far better for longer.

Exercise also has effects in the brain via BDNF, brain derived neurotrophic factor. And via increasing brain vasculature.

Aging = Decline of Physical Capability Exercise = Increase in Physical Capability

One can conserve physical capability in old age when exercising well.

People are less active because they are weaker, and they are weaker because they are less active.

Muscle helps us survive old age.

Muscles are like an exoskeleton that protects bones. An exoskeleton we can build via exercise.

A lot of old people die from falling down something. And this can be prevented by being stronger and more balanced because of exercise.

Exercise should not be singular. Becoming really world class at one thing is not good. It over trains and puts stress in the body that is bad. You should be a movement generalist. Not exceptional at any one thing, but really good at all types of movements. From dancing to running to cycling to climbing to jumping to weight lifting. We need to be training to become "Centenarians Decathlon" athletes.

Because of the decline you need to be able to do much more now, so that you can still do "the basics" when adjusting for your decline with age.

The idea is to pick what you want to be able to do in your very old age and then work backwards from there to how good you would need to be in those things now.

Build fitness now, do a strong ass routine and stay healthy and strong your entire life. Old people are not weak by default. It's old people who do not exercise enough.

We must stop pointlessly "exercising", just because we think we are supposed to, banging away on our elliptical trainer at lunch hour. I promise, you can do better. I suggest you join me and start training, with a very specific purpose, which is to be kick-ass one-hundred-year-olds.

It's training to become an "athlete" of life.

Chapter 12 - Training 101 - How to Prepare for the Centenarians Decathlon

Three things - strength, endurance (both peak and long) and stability.

Exercise helps keep mitochondria and our energy metabolism healthy. It helps the body to burn both glucose and fat better. But it depends on the type of exercise. Especially important is type 2 exercise. Straining but not too straining to completely remove the ability to have a conversation. A slight jog.

Lower intensity of exercise burns through more fats, higher intensity switches to Glucose.

Healthy mitochondria are key to both athletic performance and metabolic health.

You want metabolic flexibility. Fat is burned in the mitochondria. This is exactly what Edubily says too.

Paper: San Millán and George Brooks - energy efficiency during exercise

If lactate builds up you're exercising too hard for zone 2. Lactate monitors exist. Keep it at 1.7-2.0 millimoles. If you can talk, but it is a bit much, you're good.

Fat people often can't burn fat anymore because they became metabolically inflexible. Sports helps against that.

Glucose can be taken into cells via multiple routes. Not just insulin. There's NIMGU. Non Insulin Meditated Glucose Uptake. It's triggered when in zone 2 exercise.

Four 45 min sessions per week is minimum of zone 2 exercise.

VO2 max is the other important market. After 5-5 months of zone 2 exercise they start training VO2 max specifically. VO2 max decreases by around 10% per decade. Keeping it high is really difficult but important because it limits the things you can do.

Again you plan for the activity you want to be doing when old, then look backwards what VO2 max you would need and then train for that while being realistic.

It's a lifelong training program. You need to be a lifelong athlete.

Supplement zone 2 workout with one or two sessions of VO2 max workout. Sustain effort for 4 minutes. Then normal zone 2 until your heart rate comes down then go again, repeat 2-4 times. Recovery has to be complete before next set.

I should have a VO2 max if 58 or higher. But I probably don't...

Muscle mass and BMD bone mass density are important. Long periods of sedentary living are really bad for both. When falling and breaking a hip bone old people usually die from the effects of the sedentary life they are forced to live. Idea is to hold strength and bone mass density high so that falls are unlikely and if they happen nothing breaks.

I think of strength training as a form of retirement saving.

Like investing strength training is also cumulative, its benefits compounding.

Rucking - carrying a lot of weight up and down a hill.

Grip strength is a proxy for general strength and a good predictor for longevity weirdly enough.

Training grip strength is simple - dead hanging exercises. For as long as you can. And carrying something heavy in both hands while walking.

There are two types of strength. One where the muscle is lengthening and one where it's shortening. Concentric - shortening is easier for most people while eccentric - longening is harder to control and be strong at.

Corollary: You focus on the down phase of exercises.

Chapter 13 - The Gospel of Stability - Relearning How to Move to Prevent Injury

All the aerobic fitness or strength in the world won't help you if you get hurt and have to stop exercising for several months—or forever.

Stability is about transmitting force safely through our bodies. It's the guy who is lean, but strong, and versatile in his sets of movements. Transmitting our force correctly is the important part. Force dissipation through joints is a problem, it's what leads to injury. Stability means none or very little force dissipation it's about using the body how it's supposed to be used.

Stability is about balancing. The different sides of the body need the same strength and we need to apply the same forces evenly. Brains cheat our body to do movements but not doing them properly, lopsided due to missing strength, injuries or other such things, this creates new problems.

DNS - dynamic neuromuscular stabilization

How babies move is about learning how to move correctly automatically. Sitting and other unnatural movement patterns undo this learning. Most people can't squat because of that. We literally forget how to move our bodies.

DNS is highly personalized. www.rehabps.com and www.posturalrestoration.com are good resources.

These ideas are related to Yoga - breathing affects balance, affects stability, affects how we transmit force.

It's extremely subtle, but the way in which someone breathes gives tremendous insight to how they move their body, and more importantly, how they stabilize their movements.

Breathing should be effortless, noiseless and involve the entire diaphragm, both the chest and the belly.

Different Breathing Types: Puff Guy Sad Guy Yogini

Lie on the back. Inhale fully as quietly as possible. Then exhale through pursed lips completely before face gets tense or shoulders roll in. Pause after exhale for two seconds.

The abdomen is a cylinder and pressurizing it by breathing creates stability just like a bottle with a cap on and air in is more stable than without.

Stability is also about the feet. Toe Yoga and Toe Strength are a thing.

Thought: All of this stuff is very much akin to parkour training and known to people who do parkour. Martial arts too. And also free divers have some of those ideas. It's interesting how these different ideas combine and mix and match.

www.peterattiamd.com/outlive/videos

Feel corners of feet, big toe, small toe, inside heel, outside heel. Then lift all 10 toes, put down only the big toe. Then only the small toe. Then put down each toe, one after another from out to in and in to out.

It will take mental effort. And that's the point, regaining muscular control of the entire muscle chain. Slowly.

Really really slow cow/cat movement. Feeling vertebrae move one by one, exhale on cat, inhale on cow. It's about learning to control each segment of the spine separately and feeling how they move. It's about awareness.

Hands and how we use them is also important. Adding carrying exercises to workouts is the way to go, but again awareness of what our fingers actually do is important.

All these basic principles take time to develop. At least six months before going to heavy weights.

Stability is if what you think you are doing and what you are actually doing are the same.

All of exercise is about getting better, not only slowing decline but doing more than that.

Good Yoga Instructors can help with rewiring neuromuscular control, but most classes are too loose.

Chapter 14 - Nutrition 3.0 - You say Potato, I say "Nutritional Biochemistry"

Diet and nutrition are so poorly understood by science, so emotionally loaded, and so muddled by lousy information and lazy thinking that it is impossible to speak about them in nuanced terms at a party, or say, on social media.

Diets are highly personal, and have to be goal oriented. It's about knowing what you want to achieve and how biochemistry works and then using that knowledge adapted to your particular circumstances.

Three questions:

• Undernourished or overnourished?
• Undermuscled or overmuscled?
• Metabolically healthy or not?

Diets that compromise muscle are not ok. This includes most forms of fasting.

Nutrition is a way to fix things that have gone awry. Maintenance is a different thing and requires a different diet.

Nutrition is relatively simple, actually. It boils down to a few basic rules: don't eat too many calories, of too few; consume sufficient protein and essential fats obtain the vitamins and minerals you need; and avoid pathogens like E. Coli and toxins like mercury or lead. Beyond that we know relatively little with complete certainty.

Nutrition research isn't good. Confounding variables and small effect sizes are big problems.

After correcting for all other variables, there is no dose of alcohol that is healthy.

Chapter 15 - Putting Nutritional Biochemistry into Practice - How to Find the Right Eating Pattern for You

Whenever, whatever, in as great a quantity as we want = SAD = standard American diet = not a diet but a business model for feeding the world efficiently

Problem is that we are overnourished while malnutritioned. High calorie but low nutrients foods taste amazing.

Eat Less and eat better is the goal of any diet.

Three strategies to achieve this:

• Caloric Restriction
• Dietary Restriction
• Time Restriction

The biggest issue is if you lose muscle instead of fat. This can happen if you don't eat enough protein in the calories consumed.

Don't eat highly processed foods. Calorie intake has to closely match calorie usage. Quality is as important as quantity (because of nutrient profiles). Not eating to excess is beneficial even if otherwise eating healthy.

CGM is very useful. Average blood glucose should be around 100mg/dL or an HbA1c of 5.1%

Sleep Quality and stress levels affect glucose response very strongly.

CGM lessons:

• carbs are not equal amount of processing and fiber matters
• rice and oatmeal are glycemic
• fructose is not measured
• timing, duration and intensity of exercise matter in relation to food intake and blood sugar
• sleep is important
• stress too
• no starchy veggies are awesome
• foods high in protein and fat don't affect blood sugar levels, only high in protein affects blood sugar slightly
• effects stack in both directions
• tracking has a positive impact already

Hawthorne Effect: when watched we do better.

Protein is not used for energy only for structure. We don't store it. Standard recommendations are a joke. You lose muscle if you eat only that much. You need 3 times that if you want to build muscle, around 2.2 g / kg / day. Spread over the day.

Plant protein is less bioavailable than animal protein because it's tied up in fibers. And the amino acid combination is not ideal. So overall protein quality from plants is worse.

Certain amino acids are usually the bottleneck not "protein" generically. Things to research: DIAAS and PDCAAS. Per day: 3-4 g of leucine and lysine and 1 g methionine to conserve muscle mass, twice that if you want to increase.

Fats: 3 types - saturated fatty acids (SFA), mono unsaturated fatty acids (MUFA), poly unsaturated fatty acids (PUFA)

The differences are about how many hydrogens are in the carbon chain. I.e. how many double bonds does the carbon chain have.

PUFA are further divided in Omega 6 vs. Omega 3, based on where the hydrogen atom/double bonds is situated.

Omega 3 is further divided into marine (EPA, DHA) and non marine (ALA) variants

Most foods contain a mix of SFA, MUFA, and PUFA. The ratios are important.

Usually it's about eating more olive oil, nuts, anchovies, salmon and avocados, while cutting back on butter, lard, corn, soybean, and sunflower oil.

However literature on all of this is somewhat unclear and effect sizes are small. Problem is that it's highly individualistic. Without testing you simply don't know how fats relate to disease markers.

Fasting: Unclear benefits. If used, carefully and deliberately, like medicine almost. Fasting has benefits, starving ketosis, no insulin spikes, clearance of fat from liver, hunger disappearing. Down regulation of mTor. Activation of FOXO. Upregulation of autophagy.

Different types of fasting:

• eating windows
• alternate day fasting (ADF)

Eating windows main idea comes from studies in mice. But for mice a 16/8 fast is a whole different beast than it is for people. Because mice live less long and die when not eating for 48 hours. It's not like that in people and the main benefits come from the caloric restriction, not the up/down regulation of mTor etc. also you miss out on the protein quota. Often people loose muscle and overindulge on fastfood. Losing mass, but lean mass which is bad.

ADF people feel bad and exercise less and lose muscle too. Loss of muscle is not weighed in enough by the upregulation of mTor. You have to eat enough to maintain muscle mass.

Bad nutrition can hurt us more than good nutrition can help us.

Don't be over/undernourished and metabolically healthy and everythings alright.

Chapter 16 - The Awakening - How to Learn to Love Sleep, the Best Medicine for Your Brain

One sleepless night can create a state that is the functional equivalent of being legally drunk.

Chronic sleep debt is killing people. Fix sleep and it's easier to fix the rest.

Book Recommendation: Why We Sleep - Matthew Walker

Sleep has to be extremely essential otherwise evolution would have gotten rid of it long ago.

We are good at adapting to sleep deprivation psychologically but the long term shit effects still get us. 7 1/2 to 8 1/2 hours per night is necessary.

Bad sleep kills metabolism. Inadequate sleep changes the insulin response to be much much worse and also changes feelings of hunger by messing with Ghrelin and Leptin hormones. We feel less satiated and more hungry. Sleep is also tied to stress and cortisol. Non adequate sleep causes stress and stress reduces sleep quality. It's not only about the time spent sleeping. 11 hours or more is actually really bad, too much sleep means there is an underlying other issue, reducing sleep quality drastically. Poor sleep activates the sympathetic nervous system. It's akin to stress.

During sleep the brain cleanses itself. Neurons make way for brain fluid to wash away proteins and other metabolic junk. Hence sleep disturbances are linked to Alzheimer's.

Sleeping drugs generally don't help to procure better quality sleep, coma != sleep

Sleep apnea is a thing and it reduces sleep quality tremendously. Test for it.

Darkness is necessary for good sleep.

Modern life almost systematically destroys our ability to sleep properly.

No screens and any lights in the room where you sleep.

Coldness helps sleep. Body core temperature needs to drop.

Alcohol doesn't help sleep either.

Coffee is not a solution for poor sleep. Wrong timing is really bad. Caffeine blocks adenosine receptors, the molecule that builds up over day and makes sleep pressure happen.

Outdoors zone 2 exercise in the mornings is the way to go.

How to improve sleep:

• no alcohol
• no eating 3 hours before
• no screens 3 hours before
• no anxiety inducing activities 1 hour before
• hot bath/shower before bed
• cold bedroom or cool mattress
• completely dark room
• give yourself big time windows for sleeping
• fix wake up time with alarm
• don't obsess over sleep
• early morning exercise in sunlight

If you still can't sleep, get checked for Insomnia.

Chapter 17 - Work in Progress - The High Price of Ignoring Emotional Health

The mental side of health is as important as the physical side. Many people tend to forget that.

Physical and emotional health are intertwined. Suicide and para suicide are real dangers. Alcohol and drug abuse and things of that sort are para suicides.

Nothing else about longevity is really worth much without a some degree of happiness, fulfillment, and connection to others.

So they drift along, as their emotional misery drags their physical health down along with it.

Trauma can take different forms. There are weak and strong traumas, both can shape our lives and how we live out day to day situations. There should be no minimizing of ones own psychological traumatic experiences. Maladaptive strategies to deal with traumas are problems in adult life.

4 things:

• addictions
• codependency on another person
• habituated survival strategies (anger/rage)
• attachment disorders

Codification of mental "disorders" can be an obstacle to helping people. Stories are unique, people are different in subtle and not so subtle ways, that can't be categorized in a manual.

Proactivity on emotional issues is important. Damage compounds. Many people however are unaware that they have emotional health problems in the first place.

Book Recommendation: I don't want to talk about It - Terrence Real

Social environment is a delicate ecosystem. You need to care for it. Reframing and viewing things from the viewpoint of people around you is a powerful but hard to master tool.

Book Recommendation: The Road to Character - David Brook

Insecurity and self hatred are twisted but very real emotions that many people feel.

Self exploration is required for psychotherapy. It's often both too slow and too fast. And hard work.

Breaking the chain of negative stimulus -> negative emotion -> negative thought -> negative action is a core idea of dialectical behavior therapy (DBT).

Mindfulness is the enabler of breaking the chain.

Four pillars of DBT:

• emotional regulation
• distress tolerance
• interpersonal effectiveness
• self management

Thought: All of those are reflected in the different aspects of the 7 habits of highly effective people. Sometimes I can't believe what a powerful book this has been to have read so early. It also reminds me of Jordan Petersons 12 ideas for living a good life.

Mindfulness is distance between thought and "the self". It's space to think about an reaction and eventually the ability to reject or change the reaction.

Thought: This reminds me of the "second mistake" story from The Art of Learning - namely the woman who is missed by a car, turning to curse the car and gets hit by the next. Mindfulness is realizing that cursing at the car won't help and getting back to the safety of the sidewalk. Not getting wrapped up in automatic chains of thought. It's about removing the reflexiveness.

Pain exists often entirely in the head. We ruminate without noticing that we are doing it. Mindfulness is noting the suffering for what it is and seeing exactly where it comes from. And in so doing becoming free not to suffer as much or at all.

Behavior affects mood. And mood affects behavior. But for most people behavior is easier to control and change. We can act on it.

You need to believe that change is possible. Because it is.

Thought: This is the Growth Mindset in disguise again.

Maybe the journey isn't so much about becoming anything. Maybe it's about unbecoming everything that isn't really you, so you can be who you were meant to be in the first place. – Paulo Coelho

Epilogue

Silicon Valley style approach to longevity -> biohacking. It's not human centered but treats humans as machines. This is bad.

Longevity is meaningless if your life sucks.

Thought: This sums up the problem with Bryan Johnsons blueprint pretty much... it's scientifically accurate without being wise.

Longevity needs a reason. A why to live.

Thought: This reminds me very much of the ideas of Viktor Frankl. Man's Search for Meaning.

My obsession about longevity was really about my fear of dying. And something about having children was making my obsession with longevity even more frenetic. I was running away from death as fast as I could. Yet at the same time, ironically, I was also avoiding actually living. My tactics might have succeeded in my living longer, but my strategy was unquestionably accumulating more regrets.

Thought: Jeff Bezos's regret minimization framework question comes to mind.

It's about things to look forward too. When you have dreams, aspirations, things you still want to do, you're young. Go do them.